Rohmer pathway

The German-American biochemist Fritz Albert Lipmann (1899-1986) had discovered Coenzyme A in 1948, while working at the Massachusetts General Hospital in Boston. In 1951, Lynen succeeded at the University of Munich in the isolation of acetyl- Coenzyme A, (acetyl-CoA, the activated form of acetic acid) from yeast cells. Karl Folkers at Merck Sharp Dohme recognised in 1956 mevalonic acid as a critical unit in the terpene biosynthesis, while Lynen documented its formation from three acetyl-CoA moieties and the further route to fatty acids and terpenoids. Recently, another non-mevalonate pathway to terpe-nes (Rohmer pathway) has been discovered, which is not present in humans. 

Bacterial isoprenoid synthesis - the Rohmer pathway Current biosynthetic evidence indicates that the steps from IPP to isoprenoids in Eubacteria are the same as those in eukaryotes [62-69] (see [70-73] for literature). Especially the incorporation of C-labeled precursors into prokaryotic hopanoids, sterol surrogates in bacterial membranes (see [73] and literature cited therein), or into ubiquinone-8 [70] has revealed that the classic pathway of IPP formation starting from acetyl-CoA via acetoacetyl-CoA, HMG-CoA, MVA, MVA-P, and MVA-PP does not exist in a great variety of bacteria, including E. coli Zymomonas mobilis, Methylobacterium organophilum, Rhodopseudomonas palustris, R. acidophila, Acetobacter aceti ssp. xylinum, but also in the thylakoids of the cyanobacterium Synechocystis sp. [74]. 

Rohmer, M., The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants, Nat. Prod. Rep., 16, 565, 1999. 

Rohmer, M., Seemann, M., Horbach, S. et al. (1996) Glyceraldehyde 3-phosphate and pyruvate as precursors of isoprenic units in an alternative non-mevalonate pathway for terpenoid biosynthesis. Journal of the American... 

Disch, A., Schwender, J., Muller, C., Lichtenthaler, H.K., and Rohmer, M., Distribution of the mevalonate and glyceraldehyde phosphate/pyruvate pathways for isoprenoid biosynthesis in unicellular algae and the cyanobacterium Synechocystis PCC 6714, Biochem.., 333, 381, 1998. 

RODRIGUEZ-CONCEPTION, M., CAMPOS, N MARIA LOIS, L., MALDONADO, C., HOEFFLER, J.F., GROSDEMANGE-BILLIARD, C., ROHMER, M., BORONAT, A., Genetic evidence of branching in the isoprenoid pathway for the production of isopentenyl diphosphate and dimethylallyl diphosphate in Escherichia coli, FEBS Lett., 2000,473, 328-332. 

ROHMER, M., KNANI, M., SIMONIN, P., SUTTER, B., SAHM, H., Isoprenoid biosynthesis in bacteria a novel pathway for the early steps leading to isopentenyl diphosphate, Biochem. J., 1993,295, 517-524. 

SCHWENDER, J., SEEMANN, M LICHTENTHALER, H.K., ROHMER, M., Biosynthesis of isoprenoids (carotenoids, sterols, prenyl side-chains of chlorophylls and plastoquinone) via a novel pyruvate/glyceraldehyde 3-phosphate non-mevalonate pathway in the green alga Scenedesmus obliquus, Biochem. J., 1996, 316, 73-80. 

DUVOLD, T., BRAVO, J.-M., PALE-GROSDEMANGE, C., ROHMER, M., Biosynthesis of 2-C-methyl-D-erythritol, a putative C5 intermediate in the mevalonate independent pathway for isoprenoid biosynthesis, Tetrahedron Lett., 1997, 38, 4769-4772. 

The CPPase substrate DMAPP (15) is formed from isopentenyl pyrophosphate (IPP) (14) via the IPP isomerase reaction. It had been assumed that IPP was generated only via mevalonic acid (12) (Fig. 2), but Rohmer discovered another route, 2-C-methyl-D-erythritol 4-phosphate (13) (MEP) pathway (Fig. 2) [22, 23]. A key step in the MEP pathway is the reaction catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS), which combines hydroxyethyl thiamine pyrophosphate (hydroxyethyl TPP) generated from pyruvic acid (17) and TPP with glyceral-dehyde 3-phosphate (18) to yield 1-deoxy-D-xylulose 5-phosphate (19) containing five carbons. The mevalonate pathway operates in the cytosol of plants and animals, whereas the MEP pathway is present in the plastid of plants or in eubacteria [24-27]. 

Rohmer M (2007) Diversity in isoprene unit biosynthesis the methylerythritol phosphate pathway in bacteria and plastids. Pure Appl Chem 79 739-751... 

Lichtenthaler HK, Rohmer M, Schwender J (1997) Two independent biochemical pathways for isopentenyl diphosphate and isoprenoid biosynthesis in higher plants. Physiol Plantarum... 

Gerber E, Hemmerlin A, Hartmann M, Heintz D, Hartmann MA, Mutterer J, Rodriguez-Concepcion M, Boronat A, Van Dorsselaer A, Rohmer M, CroweU DN, Bach TJ (2009) The plastidial 2-C-methyl-D-erythritol 4-phosphate pathway provides the isoprenyl moiety for protein geranylgeranylation in tobacco BY-2 ceUs. Plant Cell 21 285-300... 

In the 1970s the biosynthesis of cannabinoids was investigated with radiolabeling experiments. 14C-labeled mevalonate and malonate were shown to be incorporated into tetrahydrocannabinolic acid and cannabichromenic acid at very low rates (< 0.02%). Until 1990 the precursors of all terpenoids, isopentenyl diphosphate and dimethyl-allyl diphosphate were believed to be biosynthesized via the mevalonate pathway. Subsequent studies, however, proved that many plant terpenoids are biosynthesized via the recently discovered deoxyxylulose phosphate pathway (Eisenreich et al., 1998 Rohmer, 1999). It was shown that the Cio-terpenoid moiety of cannabinoids is biosynthesized entirely or predominantly (>98%) via this pathway (Fellermeister et al., 2001). The phenolic moiety is generated by a polyketide-type reaction sequence. 

HK Lichtenthaler, J Schwender, A Disch, M Rohmer. Biosynthesis of isoprenoids in higher plant chloroplasts proceeds via a mevalonate-independent pathway. FEBS Lett 400 271-274, 1997. 

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